Intermediates for vitamin a

ABSTRACT

A synthesis of novel Vitamin A intermediates from beta-ionone is described as well as a conversion of the intermediates to Vitamin A. The length of the conjugated aliphatic side chain of beta-ionone is increased while still ultimately obtaining the desired trans form of Vitamin A. In general, beta-ionone is ethynylated to ethynyl-beta-ionol, the hydroxyl of which is etherified to form an ethynyl-terminated, alkoxy-substituted, beta-ionol intermediate. The intermediate is coupled through its copper derivative with a compound like chloro-isopentenyl acetate to produce a C 20  skeleton. By semi-hydrogenation, the acetylenic bond on the C 20  skeleton is converted to an ethylenic bond, and by hydrolysis the terminal ester moiety is converted to a hydroxyl group. Treatment with a strong base removes the alkoxy group to produce Vitamin A.

This is a division, of application Ser. No. 566,982, filed Apr. 10,1975, which in turn is a division of application Ser. No. 353,215, filedApr. 23, 1973, now U.S. Pat. No. 3,949,006. The latter is acontinuation-in-part of application Ser. No. 246,939, filed Apr. 24,1972, now abandoned.

Vitamin A is a known organic substance which is essential for growth andfor maintaining animal life but which cannot be synthesized by theanimal nor provide energy by itself. Because of its importance, numerousattempts have been made to synthesize Vitamin A. In 1947Hoffmann-LaRocho reported the first successful laboratory synthesis ofVitamin A, marking the culmination of what had been a formidablescientific and economic challenge to the organic chemist for severaldecades. Since that time a number of different syntheses of Vitamin Ahave been suggested but most are not considered commercially feasible.

Vitamin A is generally considered to have this formula: ##STR1##

It is important to distinguish between the cis and trans forms ofVitamin A. The trans form has much higher biological activity than anyof the possible cis forms. Likewise, compounds of the above formula inwhich all double bonds are shifted one carbon atom to the left are onlyvery slightly active.

With few exceptions, all syntheses of Vitamin A utilize beta-ionone asthe starting material. Its ready availability and the fact that,structurally, it represents about 65 percent of the desired Vitamin Amolecule, as illustrated by its following formula, make it a logicalstarting point. ##STR2##

In spite of this advantage, the subtleties involved in extending thebeta-ionone side chain to Vitamin A frustrated the efforts of numerouschemists for many years. One major difficulty with the use ofbeta-ionone as the starting material in the synthesis of Vitamin A isthe behavior of the beta-ionol group on dehydration. Normally, theextension of an alpha, beta unsaturated ketone to a longer conjugatedpolyene is accomplished through nucleophilic addition to the carbonylgroup, what is, Grignard reactions, Reformatsky reactions,ethynylations, Knoevenagel reactions, etc., resulting in a carbinolcontaining the desired attached group. The carbinol is then dehydratedto evolve the additional ethylenic bond linking the two groups. Thus, inthe case of beta-ionols, this should produce the beta-ionylidene groupbringing the molecule one step closer to Vitamin A, or: ##STR3## inwhich Y is defined as alkenyl or alkynyl, either of which can besubstituted or unsubstituted.

Unfortunately, except in special cases, dehydration of beta-ionols doesnot proceed in this direction, but rather in the opposite direction toproduce the retroionylidene group. ##STR4## This went unrecognized formany years until the early 1950's. As a result, many workers wronglyassigned beta-ionylidene structures to what were actuallyretroionylidene structures and the literature on Vitamin A synthesis atthat time was confused.

The retroionylidene structure is more thermodynamically stable than thebeta-ionylidene which is sterically hindered as the ring side chainjunction. Beta-ionols, and vinylogues thereof, always dehydrate toretroionylidenes, unless the designated Y group contains a sufficientlystrong electron-attracting group, such as --C.tbd.N, --COCl, --CHO, or--C.tbd.C--.

Although the Roche synthesis was evolved before these facts were known,it fortuitously avoided the above pitfall in dealing with intermediateswhich were not betaionols. On the other hand, the known Philips andEastman synthesis do involve beta-ionol intermediates. However, in orderto avoid retroionylidene formation, the Philips process utilizes the--C.tbd.N group, and the Eastman process employs the --CHO group. Inboth of these processes, the price for these safety factors is high. Thefinal products, the Vitamin A nitrile and Vitamin A aldehyde, have to bereconverted to Vitamin A via expensive lithium aluminum hydridereactions. The more recent BASF process, German Pat. No. 957,942,utilizes the Wittig reaction for extending the beta-ionol side chain andthus avoids the troublesome beta-ionol complications. The Wittigreaction, however, tends to be costly.

In short, the past 20 years of effort in this field has established twokey factors for providing a commercially practical synthesis of VitaminA:

1. the cost of building the C₂₀ skeleton.

2. The specificity of the chemistry involved in passing from the C₂₀intermediate to Vitamin A.

The present process provides a relatively inexpensive synthesis forforming an intermediate having a C₂₀ skeleton, particularly useful forthe synthesis of Vitamin A, and one that embodies a chemical route freeof ambiguities for conversion of the C₂₀ intermediate to Vitamin A. Thesynthesis starts with beta-ionone and forms several novel beta-ionolintermediates while avoiding formation of retroisomers as well asminimizing formation of the cis forms of Vitamin A.

In general, beta-ionone is ethynylated to ethynylbeta-ionol. Thehydroxyl of the alcohol is then etherified to form anethynyl-terminated, alkoxy-substituted, beta-ionyl intermediate. Theintermediate is coupled as by the acetylenic copper derivative with acompound like chloro-isopentenyl acetate(1-chloro-4-acetoxy-2-methyl-2-butene) to produce a C₂₀ skeleton. Theacetylenic bond on the C₂₀ skeleton is converted by semi-hydrogenationto an ethylenic bond, and the terminal ester moiety is converted byhydrolysis to a hydroxyl group.

The intermediate C₂₀ skeleton at this juncture of the process has twoisolated double bonds separated by a methylene group.

It is well recognized that a methylene group situated between two doublebonds represents a very reactive prototropic center. In the above C₂₀skeleton, strong bases would, therefore, be normally expected to removea proton (H⁺) from carbon-12 to give a carbanion and result, uponneutralization, in the conjugation of the two double bonds adjacent toit. However, it was found instead, that after formation of a carbanionat C₁₂ in the above compound, with sufficiently strong bases, the alkoxygroup was eliminated at carbon-9 to give an additional double bond.Thus, a 1,4-elimination of alcohol was effected rather than simplyisomerization of the double bonds present. The formation of theadditional double bond results in conjugation of all five double bondsin the molecule to give Vitamin A.

A general description of the process and novel intermediates isinitially given followed by specific examples of various steps of theprocess. For convenience of reference Roman numerals appearing to theleft of structural formulas are similarly used in the claims torepresent the same formulas.

Beta-ionone as the starting material is reacted with a metal acetylide,such as lithium or sodium acetylide, in a known manner to provide acompound having a terminal acetylene group and a hydroxyl group on theadjacent carbon atom, that is, the compound5-(2,6,6-trimethylcyclohexen-1-yl)-3-methyl-pent-4-en-1-yn-3-ol(ethynyl-beta-ionol), as represented by the following formula: ##STR5##A method of ethynylating beta-ionone is described in an article by W.Oroshnik and A. D. Mebane published in J.A.C.S., 71, 2062 (1949).

The ethynyl beta-ionol is next etherified at the hydroxyl group. Theprocess involves stirring the ethynyl beta-ionol with a dialkyl sulfate,such as diethyl sulfate, in an aprotic solvent such as dimethylformamide in the presence of a base such as sodium hydroxide, bariumhydroxide or sodium carbonate at room temperature for several hours.Dimethyl sulfoxide may also be used as the reaction medium. Dimethylformamide is readily recovered by distillation of the reaction mixtureunder moderate vacuum. Dimethyl formamide recoveries of at least 70percent have been obtained without difficulty. A class of compounds isobtained having the following general formula: ##STR6## in which R islower alkyl or alkenyl, such as up to 5 carbon atoms, preferably methylor ethyl, phenyl or aralkyl of up to 10 carbon atoms. An example of acompound of this class, using normal organic nomenclature, is ethyl1-ethynyl-1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)allyl ether.

A compound of Formula I is coupled with another reactant to form a basicC₂₀ skeleton of Vitamin A. Such other reactant may be the acetoxyanalogue of the chloroester of the added chain length required, forexample, the aforementioned chloro-isopentenyl acetate. Thechloroacetate is known and prepared by the chlorohydrination of isoprenein glacial acetic acid, as described in an article by W. Oroshnik and R.A. Mallory, J.A.C.S., 72, 4608 (1950).

The coupling reaction is accomplished through a preformed cuprousacetylenyl derivative. Coupling with a chloroester may not be carriedout with a copper-catalyzed Grignard reaction because of the reactivityof the Grignard reagent toward the acetate group in the chloro-acetatereactant. Organo copper compounds are inert toward esters. The cuproussalts of substituted acetylenes, unlike cuprous acetylide, have beenfound to be non-explosive and quite stable even at elevatedtemperatures.

The coupling reaction involves pre-forming a cuprous salt of thecompound of Formula I and reacting the cuprous salt with the couplingreactant in an aprotic solvent, such as dimethyl formamide. The couplingreactant may have the following formula: ##STR7## in which R¹ ishydrogen or ##STR8## R² being a lower alkyl of up to 5 carbon atoms,phenyl, substituted phenyl of up to 10 carbon atoms or an aralkyl of upto 10 carbon atoms; and R³ is a halogen. The coupling reaction resultsin a class of compounds having the following general formula: ##STR9##in which R and R¹ are as previously defined. An example of a compound ofthe class of Formula III, using carotenoid nomenclature based on theparent compound retinol, is:10,11-didehydro-9-ethoxy-9,12-dihydroretinol acetate. Optionally, thecoupling may be carried out by pre-forming the cuprous derivatives insitu through a Grignard intermediate in ether as well as in hexamethylphosphoric triamide as the aprotic solvent.

A compound of Formula III is next subjected to a semi-hydrogenation toconvert the acetylenic bond to an ethylenic bond, for example, bycatalytic means. Lindlar catalyst (5 percent palladium on calciumcarbonate modified by addition of lead) may be used, or Raney nickel maybe used as the catalyst, treated with zinc acetate and a secondaryamine, such as diethanelamine. The latter catalyst is referred to in anarticle by W. Oroshnik, G. Karmas and A. D. Mebane, J.A.C.S., 74, 295(1952). The semi-hydrogenation produces a class of compounds having thefollowing general formula: ##STR10## in which R and R¹ have the samemeanings as previously given. An example of a compound of this class,using carotenoid nomenclature, is 9-ethoxy-9,12-dihydroretinol acetate.

As indicated, the terminal group R¹ of the compounds of Formulas III andIV can comprise a number of different groups such as hydrogen, acyl(COR²) in which the alkyl group contains up to about 5 carbon atoms, orphenacyl and substituted phenacyl with up to about 10 carbon atoms, oraralkyl acyl in which the aralkyl group contains up to about 10 carbonatoms. However, the terminal OR¹ group preferably is hydroxyl to obtainVitamin A. This is accomplished by hydrolyzing the terminal ester groupor otherwise converting the terminal OR¹ group to hydroxyl to form aclass of compounds having the general formula: ##STR11## in which R hasthe same meaning as before. The hydrolysis or other treatment of theterminal group may occur at any desired time and need not follow thesequence herein given, that is after the semi-hydrogenation.

The intermediate compound of Formula V is an alkoxy substituted9,12-dihydroretinol. This compound has two isolated double bondsseparated by a methylene group (carbon-12). It is well recognized that amethylene group situated between two double bonds represents a veryreactive prototropic center. In the above compound, strong bases wouldtherefor normally be expected to remove a proton (H.sup.⊕) fromcarbon-12 to give a carbanion and result, upon neutralization, in theconjugation of two double bonds adjacent to it. However, it was found,contrary to expectations that, after formation of a carbanion at C₁₂ inthe above compound, with sufficiently strong bases, the alkoxy group waseliminated at carbon-9 to give an additional double bond. Thus, a1,4-elimination of alcohol (ROH) was effected rather than simplyisomerization of the double bonds present. The formation of theadditional double bond results in conjugation of all five double bondsin the molecule to give Vitamin A. This rearrangement and1,4-elimination of ROH may be illustrated as follows: ##STR12##

Examples of strong basic media which may be used in the presentinvention are sodamide or potassium amide in liquid ammonia, with orwithout a co-solvent. Suitable cosolvents are ether, ethylene diamine,tetrahydrofuran (THF), pentane and amide aprotic solvents such ashexamethylphosphoramide (HMPA). Other strong basic media are lithiumalkyls, e.g., methyl lithium, in ether; lithium amide in liquid ammoniaand ether, or in liquid ammonia and THF; lithium diethylamide in etheror in diethylamine; and N-lithioethylenediamine in ethylene diamine.Still others are sodium or potassium-t-butoxide in aprotic solvents[e.g., dimethylformamide (DMF)]; sodium hydride in ether;methyl-sulfinylcarbanion which is the reaction product of sodium hydridein dimethylsulfoxide (DMSO). Particularly, suitable yields have beenobtained employing sodamide in liquid ammonia with two co-solvents,e.g., ether and ethylene diamine. By the present invention, desiredconjugated pentaenes in relatively high yields, for example 75% orhigher, have been obtained.

As indicated, the treatment with a base effects an elimination of analkanol molecule from the chain structure. This vinylogousbeta-elimination of methanol, ethanol, etc., is indeed quite unexpectedand surprising, since elimination of a methoxy or ethoxy group wouldnormally be expected to occur only under acidic conditions through acarbonium ion mechanism rather than under the basic conditions of thepresent invention. The final polyene evolved is also quite stable in thebasic medium. Thus, reverting to the use of the previous formulas, thefinal step in the synthesis of Vitamin A from a compound of Formula Vbecomes: ##STR13##

The following examples only illustrate the invention and are notintended to limit the claims. Temperatures are on the Centigrade scaleunless otherwise indicated.

EXAMPLE 1 Preparation of Ethyl Ether of Ethynyl-beta-ionol, Formula I

Beta-ionone was reacted with lithium acetylide in a known manner toproduce ethynyl-beta-ionol. The etherification of tertiary alcohols isknown to be difficult and usually results in poor yields. When an --OHgroup is hindered, diminishing its tendency to form alkoxide ions,additional difficulty is encountered upon attempted etherification.Unfortunately, all of these factors prevail in ethynyl-beta-ionol.

Ethynyl-beta-ionol has been successfully converted in the presentinvention to its lower alkyl ethers by use of alkyl sulfates, using anaprotic solvent such as dimethyl sulfoxide (DMSO) or dimethyl formamide(DMF) in a basic medium, using a base such as NaOH or Ba(OH)₂. Theyields are excellent, running around 90 percent. In one example, thefollowing components were used:

    ______________________________________                                        Ethynyl-beta-ionol                                                                            65.7      g.      (0.3 mole)                                  Ethyl sulfate   138.6     g.      (0.9 mole)                                  Sodium hydroxide (97%)                                                         pellets        37.0      g.      (0.9 mole)                                  Dimethyl sulfoxide                                                                            200       ml.                                                 ______________________________________                                    

The components were placed in a one liter, 3-neck flask equipped with astirrer, thermometer and nitrogen inlet tube. The mixture was stirredgently with sufficient speed to move the pellets of NaOH about. Heat wasslowly evolved. With the aid of only minor outside cooling, thetemperature was maintained at about 35° (33° - 37°). After 6 hours ofstirring, a second liquid phase appeared and the reaction was stopped bydecanting the liquids from the unreacted NaOH. At this point, about 5 to10 grams of unreacted NaOH remained. The flask was washed with acetoneand the washings added to the reaction product. To the mixture was thenadded 75 ml. of concentrated aqueous NH₄ OH and the whole allowed tostand overnight to destroy unreacted ethyl sulfate.

The following morning the mixture was poured into two liters of brine ina large separating funnel and the precipitated oil taken up in hexane.The aqueous layer was re-extracted once with more hexane. The combinedhexane extracts were washed once with water, dried over anhydrous sodiumsulfate and concentrated under vacuum to an oil. This oil was thendistilled through a 10 inch jacketed Vigreaux column at 0.1 mm pressure.The following fractions were obtained:

    ______________________________________                                        Fraction I                                                                              70-71° / 0.1 mm-2.9 g.                                                                   n.sub.D 20                                                                            1.4834                                    Fraction II                                                                               71° / 0.1 mm-58.3 g.                                                                   n.sub.D 20                                                                            1.4880                                    Fraction III                                                                            71-72° / 0.1 mm-7.6 g.                                                                   n.sub.D 20                                                                            1.4898                                            Distillation residue - 4.1 grams.                                     ______________________________________                                    

The infrared spectrum analysis of the main fraction II showed no freehydroxyl group. The ultraviolet spectrum analysis showed only a singlemaximum λ_(m) 236 mμ, characteristic of the beta-ionol chromophere.However, some ethynyl-beta-ionol may be present in the crude productand, if so, may be removed by the procedure of Example 2.

EXAMPLE 2 Preparation of Ethyl Ether of Ethynyl-beta-ionol, Formula I

    ______________________________________                                        The reaction mixture comprised:                                               Ethynyl-beta-ionol   130.5      g.                                            Ethyl sulfate        278        g.                                            Hydrated barium hydroxide                                                                          222        g.                                            Dimethyl sulfoxide   400        g.                                            ______________________________________                                    

The mixture was maintained at 24° to 27° for about 11 hours. Afterpercolating the worked up reaction mixture through a column of 650 gramsof alumina and washing with pentane, a product of 125.7 grams wasobtained of the ethyl ether of ethynyl-beta-ionol. The yield had aboiling point of 74° at 0.18 mm. of mercury, n_(D) 24 1.4842.

The total distillate consisted of a single fraction. It was free ofhydroxyl as evidenced by no hydroxyl band in its infrared curve. Thedistillate had a strong acetylene hydrogen band at 3.0-3.1 mμ, and theether doublet at 9.12 and 9.34 mμ. The ultraviolet curve showed a peakat 236 mμ showing the beta-ionyl group to be intact.

On elution of the column of alumina with diethyl ether, a yield wasobtained of 9.2 grams of unchanged ethynylbeta-ionol.

EXAMPLE 3 Preparation of Methyl Ether of Ethynyl-beta-ionol, Formula I

    ______________________________________                                        Ethynyl-beta-ionol                                                                            68.1      g.      (0.315 mole)                                Methyl sulfate  119       g.      (0.945 mole)                                Hydrated barium                                                                hydroxide      96.4      g.      (0.506 mole)                                Dimethyl formamide                                                                            215       ml.                                                 ______________________________________                                    

The ionol, barium hydroxide and dimethyl formamide are placed in a oneliter, three-necked flask equipped with a mechanical stirrer,thermometer and nitrogen inlet tube. Under steady stirring, the methylsulfate is added dropwise at 10°. Reaction is very slow at thistemperature. On raising the temperature to 17°, heat begins to evolve.By external cooling, the temperature was maintained at 20°-21°. Within1.5 to 2 hours most of the barium hydroxide had dissolved and theexothermic effect was gone. Stirring was continued at 19° to 20° forfour hours.

The reaction mixture was then poured into two liters of 5 percentaqueous ammonium hydroxide and 500 ml. of hexane. A precipitate ofbarium salts made separation difficult, and the precipitate was removedby filtration. The hexane layer was removed, dried over anhydrous sodiumsulfate, and concentrated under vacuum.

The residual oil was distilled, and these fractions were obtained:

    ______________________________________                                        Fraction I                                                                                59° / 0.07 mm-0.2 g.                                                                   n.sub.D 20                                                                            1.4960                                    Fraction II                                                                             59-60° / 0.07 mm-61.4 g.                                                                 n.sub.D 20                                                                            1.4971                                    Fraction III                                                                            59-60° / 0.07 mm-1.8 g.                                                                  n.sub.D 20                                                                            1.5015                                    ______________________________________                                    

The infrared spectrum of fraction 11 showed some free hydroxyl present,presumably from unreacted ethynyl ionol.

EXAMPLE 4

Separation of the ether of either Examples 1 or 2, was also obtained bypercolating a pentane or hexane solution of the reaction product througha column having granular alumina (Alcoa F-20) in an amount of 4 to 5times the weight of the crude product. Unreacted ethynyl-beta-ionol isretained on the column while desired ether passes through on washingwith pentane or hexane. Unchanged ethynyl-beta-ionol was then recoveredby eluting the column of alumina with diethyl ether.

EXAMPLE 5 Coupling Reaction, Preparation of Formula III

Alkylation of a compound of Formula I having a terminal acetylene groupwith a chloro-ester via the acetylenic Grignard derivative isimpractical, since the Grignard reagent reacts more readily with theester group, such as contained in the chloro-acetate. In the presentinvention, the acetylene moiety is first converted to the copperderivative. Such compounds are inert toward esters but can displace thehalide from organic halides. In this example, the following componentswere used:

    ______________________________________                                        Ethynyl-beta-ionol ethyl ether                                                                   12.3     g. (0.05 mole)                                    Magnesium          1.4      g.                                                Ethyl bromide      7.5      g.                                                Tetrahydrofuran    50       ml.                                               Cuprous chloride   6.6      g.                                                Hexamethyl phosphoric tri-amide                                                                  100      ml.                                               1-chloro-4-acetoxy-2-methyl-2-                                                 butene            12.5     g.                                                ______________________________________                                    

In a three-necked flask fitted with a mechanical stirrer, condenser,thermometer and nitrogen inlet tube, the ethyl magnesium bromide wasprepared in 40 milliliters of the tetrahydrofuran in a conventionalmanner. The acetylenic ether was then added at room temperature usingthe last 10 milliliters of tetrahydrofuran. Evolution of ethane startedat once, and the mixture was stirred and heated for two hours when gasevolution ceased. To the solution of acetylenyl Grignard reagent thusformed, the hexamethyl phosphoric tri-amide was added at roomtemperature.

The reaction flask was then flushed with nitrogen and under a positivepressure of nitrogen, the cuprous chloride was added at roomtemperature. It dissolved immediately. The mixture was then stirred at65° for 30 minutes and the chloroacetoxy methylbutene added at once. Themixture was then stirred at 83° to 92° for six hours under nitrogen.

The reaction was quenched by pouring the mixture into one liter of anaqueous solution of 10 percent NH₄ Cl and 5 percent NH₄ OH, layered with300 ml. of pentane. After thorough mixing, the pentane layer wasseparated, dried over sodium sulfate and concentrated under vacuum. Toremove unreacted chloroisopentonyl acetate, 50 ml. of diethyl amine wereadded and the solution allowed to stand at room temperature overnight.

The following morning a precipitate of Et₂ NH.HCl was present. Themixture was washed twice with brine, five times with 15 percent aceticacid, then with water, and finally with NaHCO₃ solution. After dryingwith sodium sulfate, the product was concentrated under vacuum.Unchanged starting ether was removed by treatment with neutral alumina(Alcoa F-20).

The infrared spectrum of the product obtained showed the presence of theacetate group and the ether group. Its ultraviolet spectrum showed asingle maximum at 236 mμ, characteristic of the beta-ionol group diene.

EXAMPLE 6

Alternatively in Example 5, should the product show the presence ofunreacted chloride after the diethylamine treatment, the chloride shouldbe removed as follows prior to distillation to avoid decomposition.

The reaction product at the stage indicated was passed through a columnof neutral alumina without making any attempt at chromatographicfractionation. The chloride was removed and the product recovered bywashing the column of alumina with diethyl ether. The wash product wasthen distilled under high vacuum and collected at 98° to 105° at 0.001mm. mercury, n_(D) ²² 1.4950. This product was the acetate form ofFormula III. The infrared spectrum showed allylic ester bands at 5.75 μ,8.16 μ, and 9.77 μ. The ether doublet was at 9.1 μ and 9.21 μ. Theultraviolet showed the beta-ionyl chromophore at λ_(m) 236 mμ.

EXAMPLE 7

This example illustrates a further technique for treating the crudereaction product of Example 5 obtained from the coupling reaction. Suchreaction product was concentrated under vacuum and dissolved in 2percent methanolic sodium hydroxide. The solution was then allowed tostand at room temperature under a blanket of nitrogen for 12 hours. Theunreacted chloride present and the ester groups on the coupling productwere thereby hydrolyzed.

The mixture was next quenched with water and the resulting precipitatedoil taken up in pentane, dried with sodium sulfate and distilled undervacuum. The product was collected at 100°0 to 110° at 0.001 mm ofmercury, n_(D) ²⁴.5 1.5060. The infrared spectrum showed a prominenthydroxyl band at 2.9 μ and no ester bands. The ultraviolet spectrumshowed the typical beta-ionyl chromophore, λ_(m) 236 mμ. The resultingproduct corresponded to a compound of Formula III in which R¹ washydrogen.

EXAMPLE 8 Semi-Hydrogenation of Coupling Product, Preparation of FormulaIV

A solution of 2.6 grams of an acetate compound of Formula III in 50 ml.of hexane was stirred under hydrogen with 1.56 grams of lindlar catalyst(5 percent Pd on CaCO₃) at 22°. Absorption of hydrogen ran at about 6.0ml./min. At the theoretical end-point, 176 milliliters of hydrogen at22°, the rate of absorption had fallen to 0.8 ml./min. The catalyst wasfiltered off and the hexane removed under vacuum. The product was alight yellow oil; the yield was 2.52 g.

The infrared spectrum of this oil showed the presence of the acetate andether groups, indicating no hydrogenolysis had occurred. The ultravioletspectrum of the oil showed a single maximum at 236 mμ, showing thebetaionyl diene still intact.

EXAMPLE 9 Hydrolysis of Semi-Hydrogenated Coupling Product, Preparationof Formula V

The semi-hydrogenated, acetate coupled product of Example 8 wasdissolved in a one percent solution of sodium hydroxide in methylalcohol. The solution was allowed to stand about 12 hours at roomtemperature under a blanket of nitrogen. The hydrolysis was complete asshown by the total absence of ester bands in an infrared analysis.

EXAMPLE 10 De-ethanolation of the Semi-Hydrogenated Hydrolyzed CouplingProduct, Preparation of Vitamin A

The product of Example 9, was placed in anhydrous ether solution and themixture added to a suspension of freshly prepared sodamide in liquidammonia in a weight ratio of about 2.28 product:25 ether:1.36sodamide:100 ammonia. At minus 40° no reaction appeared to take placeother than the formation of the alkoxide of the starting material. Onraising the temperature to minus 30°, the reaction mixture turned a deepopaque purple which remained for the duration of the run. After 2 hoursthe reaction mixture was quenched with ammonium chloride.

Separation of Vitamin A from the product obtained was achieved byacetylating the total reaction product using pyridine-acetic anhydrideat room temperature and chromatographing on alumina neutralized withacetic acid. A fairly clean separation was achieved. The Vitamin Aacetate fraction was sufficiently pure to become crystallized frompentane at minus 15° when seeded with a pure Vitamin A acetate crystal.

As determined chromatographically, the results of this example were asfollows in weight percent.

    ______________________________________                                        Vitamin A (as acetate)          62%                                           Ethylenic coupling product of                                                  Example 4                      35%                                           Unknown hydrocarbons                                                                              about        3%                                           ______________________________________                                    

When the Vitamin A acetate was converted to the alcohol form of VitaminA, the final product showed the characteristic infrared and ultravioletabsorption curves for Vitamin A. Similar results were obtained using ascosolvents (with the liquid ammonia) ethylene diamine and ether;pentane; tetrahydrofuran; diethylamine and hexamethylphosphoramide.

By the present process the vicissitudes and uncertainties ofacid-promoted carbonium ion reactions leading to isomeric mixtures areavoided. In addition the Vitamin A evolves into a basic medium where itsstability is much enhanced over that in an acid medium.

I claim:
 1. A compound having the formula: ##STR14## in which R is loweralkyl, lower alkenyl, phenyl, or aralkyl of up to 10 carbon atoms, andR¹ is hydrogen or ##STR15## R² being lower alkyl, phenyl or aralkyl ofup to 10 carbon atoms.
 2. The compound of claim 1 which is10,11-didehydro-9-ethoxy-9,12-dihydroretinol acetate.
 3. The compound ofclaim 1 which is 10,11-didehydro-9-ethoxy-9,12-dihydroretinol.
 4. Thecompound of claim 1 which is10,11-didehydro-9-methoxy-9,12-dihydroretinol acetate.
 5. The compoundof claim 1 which is 10,11-didehydro-9-methoxy-9,12-dihyroretinol.